Effect of Pregnenolone vs Placebo on Self-reported Chronic Low Back Pain Among US Military Veterans

Abstract

IMPORTANCE In response to the national opioid public health crisis, there is an urgent need to develop nonopioid solutions for effective pain management. Neurosteroids are endogenous molecules with pleotropic actions that show promise for safe and effective treatment of chronic low back pain. OBJECTIVE To determine whether adjunctive pregnenolone has therapeutic utility for the treatment of chronic low back pain in Iraq-and Afghanistan-era US military veterans. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled clinical trial that enrolled for 42 months, from September 2013 to April 2017. Participants were Iraq-and Afghanistan-era veterans aged 18 to 65 years with chronic low back pain who received treatment in the Durham VA Health Care System in Durham, North Carolina, over 6 weeks. Data analysis began in 2018 and was finalized in March, 2019. INTERVENTIONS Following a 1-week placebo lead-in, participants were randomized to pregnenolone or placebo for 4 weeks. Pregnenolone and placebo were administered at fixed, escalating doses of 100 mg for 1 week, 300 mg for 1 week, and 500 mg for 2 weeks. MAIN OUTCOMES AND MEASURES The primary outcome measure was the change in mean pain intensity ratings from a daily pain diary (numerical rating scale, 0-10) between visit 3 (baseline) and visit 6. Secondary outcomes included pain interference scores (Brief Pain Inventory, Short Form). Preintervention and postintervention neurosteroid levels were quantified by gas chromatography with tandem mass spectrometry. Hypotheses tested were formulated prior to data collection. RESULTS A total of 94 participants (84 [89.4%] male; mean [SD] age, 37.5 [9.8] years; 53 [56.4%] of self-reported Caucasian race and 31 [33.0%] of self-reported African American race) were included. Forty-eight participants were randomized to pregnenolone and 52 to placebo, of whom 45 and 49, respectively, were included in baseline demographic characteristics secondary to noncompliance with medications as per protocol. Veterans randomized to pregnenolone reported significant reductions in low back pain relative to those randomized to placebo. Baseline unadjusted mean (SE) pain diary ratings were 4.83 (0.23) and 5.24 (0.22) for the placebo-and pregnenolonetreated groups, respectively (baseline unadjusted mean [SE] ratings for pain recall were 4.78 [0.24] and 5.15 [0.23], respectively). Unadjusted mean (SE) ratings following treatment (visit 6) were 4.74 (0.26) in the placebo group and 4.19 (0.30) in the pregnenolone-treated group. Unadjusted mean (SE) ratings for pain recall following treatment were 4.86 (0.27) for placebo and 4.18 (0.29) for pregnenolone. Least-square mean (LSM) analysis showed that pain scores significantly improved in (continued) Key Points Question Does adjunctive treatment with pregnenolone improve chronic low back pain in Iraq-and Afghanistan-era US military veterans? Findings The use of pregnenolone in this randomized, double-blind, placebocontrolled clinical trial in 94 veterans with chronic low back pain resul...

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Neuroactive Type-A γ-Aminobutyric Acid Receptor Allosteric Modulator Steroids from the Hypobranchial Gland of Marine Mollusk, Conus geographus

“…6,7 This includes promising treatments for pain that have lower addiction potential than currently approved agents. 8,9 The molecular mechanisms of key neuroactive steroids have been described in great detail. Most known neurosteroids act on a wide range of membranes and intracellular receptors, which mediate their multiple biological effects.…”

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